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Biomedical subjects

R E White

Publications and source records attributed to R E White.

At least 91 records · Page 5Linked to original sources
PubMed1986

Alpha 1- and alpha 2-adrenoceptor agonist-induced contraction in rat mesenteric artery upon removal of endothelium.

Contractile response to norepinephrine, methoxamine and clonidine were determined in rat mesenteric arteries with and without an intact endothelium. Removal of the endothelial cell layer markedly enhanced the maximum contractile effect of norepinephrine (2.8 fold), methoxamine (4.0 fold) and clonidine (13.0 fold). Furthermore, there was a significant decrease in the EC50 values for these agonists. These findings indicate that both alpha 1- and alpha 2-adrenoceptor agonists can induce contraction of mesenteric arteries which is modulated by the endothelial cell layer.

Adrenergic alpha-Agonists↗
PubMed1986

Suppression of a pokeweed mitogen-stimulated plaque-forming cell response by a human B lymphocyte-derived aggregated IgG-stimulated suppressor factor: suppressive B cell factor (SBF).

The mechanisms whereby formed immune complexes (IC) or immunoglobulin aggregates can suppress further antibody production were explored by culturing normal human peripheral blood mononuclear leukocytes (PBL) with heat-aggregated IgG (HAIgG) and collecting the culture supernatants at 24 hr. These supernatants were found to suppress a pokeweed mitogen (PWM)-induced rheumatoid factor plaque-forming cell (RF-PFC) response in normal individuals. PWM-induced anti-trinitrophenylated sheep red blood cell (TNP-SRBC) PFC were also inhibited by suppressor supernatants from HAIgG-stimulated PBL, suggesting that the polyclonal PFC response was inhibited by a suppressor factor. The suppressor factor inhibited PWM stimulated RF-PFC throughout the culture period, but suppression was maximal at the peak of the RF-PFC response. Suppressor factor was only effective at the initiation of cultures, suggesting that it inhibited early events in the PWM-stimulated RF-PFC response. Molecular weight determination of the suppressor factor by differential membrane fractionation suggested a m.w. range of 30,000 to 50,000, and chromatography on Sephadex G-100 showed a peak activity at an approximate m.w. of 32,000. Studies suggested the factor was not an interferon. Depletion of T lymphocytes by E rosetting and macrophages/monocytes by G-10 adherence did not affect the generation of suppressor factor. Depletion of T lymphocytes (OKT4, OKT8) and NK cells (Leu-11b) by antibody-dependent, complement-mediated cytotoxicity also did not affect the generation of suppressor factor. Depletion of B lymphocytes with OKB7 resulted in the generation of significantly less suppressor factor. Suppression produced by unstimulated purified B lymphocytes was approximately one-half that seen when B lymphocytes were stimulated with HAIgG. Differential membrane fractionation studies suggested that only HAIgG-stimulated B cell cultures contained peak activity in the 30,000 to 50,000 m.w. fraction. Supernatants from unstimulated purified T cells also generated suppression, which was approximately one-half of that seen with HAIgG-stimulated B cells, but no increase in suppressor activity was seen in T cell cultures after incubation with HAIgG. These studies demonstrate that HAIgG is capable of stimulating B lymphocytes to produce a lymphokine, suppressive B cell factor (SBF), which is capable of suppressing a polyclonal PFC response. SBF may be important in feedback control of human immunoglobulin production.

Antibody Formation↗
PubMed1986

Decreased suppressive B cell factor (SBF) in rheumatoid arthritis: evidence for a defect in B cell autoregulation.

Rheumatoid arthritis (RA) is a disorder characterized by defective immunoregulation. Hypergammaglobulinemia, circulating immune complexes (IC), and autoantibodies such as rheumatoid factor (RF) are common serum abnormalities. To assess IC-mediated feedback suppression in RA, we evaluated the ability of a suppressive B cell factor (SBF) generated by culturing heat-aggregated IgG (HAIgG) with peripheral blood mononuclear leukocytes (PBL) from patients with RA and normal controls to suppress the pokeweed mitogen (PWM)-induced RF plaque-forming cell (PFC) response of normal PBL. RA patients generated less SBF than age-matched controls. Background suppression (supernatants obtained from PBL cultured without HAIgG) was similar in the RA patients and age-matched controls. To determine the effects of nonsteroidal antiinflammatory drug (NSAID) therapy on suppression, RA patients and age-matched controls were studied before and after NSAID therapy. NSAID therapy significantly reduced background suppression in RA patients who were not on immunosuppressive drugs and in age-matched controls, but there was no effect on SBF in RA patients or controls. There was a small increase in background suppression when NSAID were administered to RA patients on immunosuppressives, suggesting an ameliorative effect of NSAID in this group of patients, which tended to increase their level of suppression when compared with RA patients only on NSAID. Spontaneous RF-PFC were measured in normal controls and RA patients and were compared with suppressor activity. There were increased numbers of spontaneous RF-PFC in RA patients. Total suppressor activity was greatest in young adult controls, who also had the least RF-PFC. The percentage of suppression correlated inversely with the number of RF-PFC in patients and controls. Additionally, disease activity in RA as measured by total joint count and erythrocyte sedimentation rate (ESR) was shown to correlate inversely with total suppressor activity. We conclude that the PBL from patients with RA produce decreased SBF after HAIgG stimulation and that loss of suppression is also associated with aging. This study suggests a defect in IC-stimulated B cell suppressor activity in RA leading to decreased ability to suppress antibody and further IC formation. The combination of increased RF-PFC and decreased SBF suggests that there is defective B cell autoregulation in RA, which may be involved in the pathogenesis and chronicity of this disease.

Anti-Inflammatory Agents↗
PubMed1986

Active site mechanics of liver microsomal cytochrome P-450.

For a set of 10 para-substituted toluene derivatives, three enzymatic constants were determined describing their interaction with purified rabbit liver microsomal P-450LM2. The three constants were the catalytic rate constant (Kcat) for hydroxylation, the apparent dissociation constant (Kd) for the enzyme-substrate complex, and the interaction energy (delta Gint) between the substrate-binding and spin-state equilibria. The para-substituents of the toluene substrates were: hydrogen, fluoro, bromo, chloro, iodo, nitro, methyl, cyano, isopropyl, and t-butyl. Linear free energy correlations were sought between the enzymatic constants and several physical constants of the individual substrate molecules. These correlations would be useful both for empirical prediction purposes and for insight into active site chemistry and mechanics. Catalytic rates were correlated by a linear combination of the Hansch pi hydrophobic constant and the Hammett sigma value. A deuterium isotope effect (DV) of 2.6 for d8-toluene compared to d0-toluene confirmed that hydrogen abstraction was partially rate-limiting with this series of substrates. Apparent dissociation constants were predicted by a linear combination of the molar volume and pi, while the spin-state interaction energies were best predicted by a linear combination of the Hansch pi hydrophobic constant and the reciprocal of the dielectric constant.

Animals↗
PubMed1986

Enhanced relaxation response of canine coronary artery to isoproterenol and salbutamol after removal of endothelial cells.

The importance of the endothelium for isoproterenol- and salbutamol-induced relaxation of canine coronary artery was examined. The relaxation effect of isoproterenol and salbutamol was significantly enhanced (P less than 0.05) upon removal of the coronary artery endothelium. In contrast, the relaxation effect of acetylcholine was completely abolished. These results indicate that canine coronary endothelium modulates beta-adrenoceptor-mediated relaxation, and that the role of the endothelium in agonist-induced relaxation of vascular smooth muscle appears to be heterogeneous.

Acetylcholine↗
PubMed1986

Resection of the distal ulna with and without implant arthroplasty in rheumatoid arthritis.

Eighteen patients who had rheumatoid wrist surgery with resection of the distal ulna, with or without implant arthroplasty, were reviewed at an average follow-up of 32 months. Subjective and objective clinical findings did not confirm any advantage to the routine use of implant arthroplasty of the distal ulna. Moreover, a bone resorptive process, which was identified in all implant cases, may cause clinical symptoms and prosthetic instability and may warrant reoperation. The histologic findings supported a granulomatous reaction to a foreign body as a cause of the resorptive process. Histologic examination showed a synovial type of membrane and the feasibility was raised of an enzymatic cause.

Adult↗
PubMed1986

Follow-up chest radiographs in Vietnam veterans: are they useful?

Agent Orange exposure and its long-term health consequences on Vietnam veterans have been widely discussed in the past few years. Myriad physical and mental disabilities have been studied with regard to exposure to various herbicides. The number of persons potentially exposed is large, since 2.4-2.8 million U.S. military personnel served in Vietnam. A case-control study was undertaken to determine if persons who served in the U.S. military in Vietnam have either cardiovascular or pulmonary effects that can be demonstrated on long-term follow-up chest radiographs. Information regarding military service in Vietnam was obtained from interviews and, in some cases, review of military records. Vietnam veterans did not have an increased prevalence of abnormalities on follow-up chest radiographs. A subset of Vietnam veterans who had greater estimated opportunities for Agent Orange exposure also did not appear to be at greater risk than the control population.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1986

Supersensitivity and endothelium dependency of histamine-induced relaxation in mesenteric arteries isolated from diabetic rats.

Diabetes mellitus is known to produce alterations in vascular reactivity. In the present study we have examined the effects of short-term diabetes on histamine-induced relaxation of isolated mesenteric arteries, and the role of the endothelial cell layer in this response. Removal of the endothelium completely abolished the histamine relaxation effect in both diabetic and age-matched control rats. In contrast, vessels isolated from streptozotocin-diabetic rats were supersensitive to histamine, and this relaxation was mediated only through the H1-receptors. The present findings suggest that histamine-induced relaxation of rat mesenteric arteries is dependent upon endothelial cell processes which are enhanced in arteries from STZ-diabetic rats.

Animals↗
PubMed1985

Chemical characterization of protein-protein interactions between cytochrome P-450 and cytochrome b5.

Native cytochrome b5 interacts with either RLM5 or LM2 to form tight equimolar complexes (Kd = 250 and 540 nM, respectively) in which the content of high spin cytochrome P-450 was substantially increased. Cytochrome b5 caused 3- and 7-fold increases in the binding affinities of RLM5 and LM2 for benzphetamine, respectively, and benzphetamine decreased the apparent Kd for cytochrome b5 binding. Upon formation of the ternary complex between cytochromes P-450, b5, and benzphetamine the percentage of cytochrome P-450 in the high spin state was increased from 28 to 74 (RLM5) and from 9 to 85 (LM2). Cytochrome b5 caused 13- and 7-fold increases in the rate of RLM5- and LM2-dependent p-nitroanisole demethylation, respectively. Amino-modified (ethyl acetimidate or acetic anhydride) cytochrome b5 produced results similar to those obtained above with native cytochrome b5. In contrast, modification of as few as 5 mol of carboxyl groups/mol of amidinated cytochrome b5 resulted in both a substantial loss of the spectrally observed interactions with either cytochrome P-450 LM2 or cytochrome P-450 RLM5, and in a loss of the cytochrome b5-mediated stimulation of p-nitroanisole demethylation catalyzed by either monooxygenase. In further studies, native and fully acetylated cytochromes b5 reoxidized carbonmonoxy ferrous LM2 at least 20 times faster than amidinated, carboxyl-modified cytochrome b5 derivatives. In contrast, amidination, or acetylation of amino groups, or amidination of amino groups plus methylamidination of the carboxyl groups did not appreciably slow the rate of reduction of the cytochrome b5 by NADPH-cytochrome P-450 reductase. Collectively, the results provide strong evidence for an essential role of cytochrome b5 carboxyl groups in functional interactions with RLM5 and LM2.

Animals↗
PubMed1985

Enhancement of alpha-1 and alpha-2 adrenergic agonist-induced vasoconstriction by removal of endothelium in rat aorta.

It is well known that the vascular endothelial cell layer plays an essential role in the vasodilatory response of several agents. In this study we have investigated the possibility that the endothelium may also modulate alpha adrenergic agonist-induced vasoconstriction. The responses of rat aortae to selective alpha-1 and alpha-2 adrenergic agonists were studied. Removal of the endothelium did not significantly alter the maximum contractile response to norepinephrine. However, the maximum responses to selective alpha-1 agonists (phenylephrine and methoxamine) were increased 2-fold. The vasoconstrictor effects of both clonidine and B-HT920 (selective alpha-2 agonists) were enhanced 5- to 7-fold after removal of the endothelial cell layer. The sensitivity of the tissue, as reflected by the EC50 value, to each alpha adrenergic agonist was enhanced in the absence of endothelium. An explanation for the present results is that alpha-1 and alpha-2 adrenergic agonists activate adrenoceptors in the endothelial cells and thereby may promote the release of a relaxing factor to inhibit vascular smooth muscle contraction. Removal of the endothelium would abolish release of this putative inhibitory substance and adrenergic agonist would activate only adrenoceptors in the muscle to cause vasoconstriction. On the other hand, endothelial cells may function as an uptake site for the various adrenergic agonists. Ablation of this uptake process could conceivably result in a greater effective concentration of the agonist in the receptor area and thus promote a stronger vasoconstrictor effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1984

Regioselectivity in the cytochromes P-450: control by protein constraints and by chemical reactivities.

Three alicyclic compounds (D-camphor, adamantanone, adamantane) were found to be hydroxylated by the cytochrome P-450 isoenzymes P-450cam and P-450LM2. With P-450cam as the catalyst only one product was formed from each of the substrates: 5-exohydroxycamphor, 5-hydroxyadamantanone, and 1-adamantanol. With P-450LM2 as the catalyst, two or more isomeric products were formed from each substrate: 3-endo-, 5-exo-, and 5-endo-hydroxycamphor; 4-anti- and 5-hydroxyadamantanone; and 1- and 2- adamantanol. The products from P-450cam hydroxylations were found to be isosteric with one another, suggesting that each of them was attacked at a topologically congruent position within a rigid enzyme-substrate complex. The distribution of products from P-450LM2 hydroxylations, on the other hand, were similar to the distributions expected during solution-phase hydroxylations. Thus, it would appear that the complex which P-450LM2 forms with its substrate allows considerable movement of the substrate molecule, such that most of the hydrogens in the substrate are exposed to the enzymatic hydrogen abstractor. Under these conditions, the distribution of products more nearly reflects the rank order of chemical reactivities of the various hydroxylatable positions, with only a moderate protein-based steric constraint being expressed. These suggestions were also evident in the tightness of binding of the substrates to the two enzymes and in the magnitude of coupling between the substrate binding and the spin-state equilibria. Thus, the product from P-450cam-catalyzed hydroxylation may be predicted by a consideration of the relation of the topology of the prospective substrate to that of D-camphor. The products from P-450LM2-catalyzed hydroxylations, on the other hand, may be approximately predicted from the chemical reactivities of the various abstractable hydrogens in the prospective substrate.

Adamantane↗